This application will provide Timothy Shepherd, M.D. /Ph.D. with a focused training period during which he will refine the skills necessary to become an independent investigator in translational biomedical imaging with a focus on detection of asymptomatic Alzheimer's disease pathology. The career development plan will increase Dr. Shepherd's knowledge and skills in 1) pathologic and clinical manifestations of Alzheimer's disease (AD), 2) advanced MRI techniques for clinical imaging, and 3) clinical research methodology (including training in scientific integrity and the responsible conduct or research). This will be achieved via highly-structured mentoring, multidisciplinary coursework and seminars across multiple institutions at New York University (NYU). Mentorship will be provided by Fernando Boada, Steven Ferris and Thomas Wisniewski, who are each internationally recognized for their contributions to advanced MRI techniques, clinical and pathological changes in early Alzheimer's disease respectively. Dr. Shepherd also will be mentored by Robert Grossman, the Dean of NYU School of Medicine, a highly-successful clinician- scientist and role model in Dr. Shepherd's clinical specialty. Els Fieremans, a key collaborator is an expert in diffusion kurtosis MRI and modeling. An advisory committee will provide quarterly feedback to Dr. Shepherd and assess his progress so that he meets his training objectives, produce high quality data and publications, and develops a competitive application for RO1 funding at the end of the K23 career development period. The K23 research plan will test the overall hypothesis that targeted high-resolution MRI can distinguish pathological stages of Alzheimer's disease (AD) in different medial temporal lobe (MTL) structures known to be affected early in the disease process. Previous work has demonstrated that structural MRI can be sensitive to the local functional organization of normal tissue and suggests AD pathology changes to tissue organization also will be detectable. The project consists of 2 aims; 1) correlate the hallmarks of AD pathology to changes in the MRI properties (diffusion kurtosis, white matter integrity and T2) of MTL substructure tissue samples (e.g. entorhinal cortex), and 2) use targeted MRI of the MTL to characterize MRI property changes in a cross- sectional study of subjects categorized to different preclinical and clinical stages of AD. This project incorporates multiple innovations that suggest the impact of structural MRI as a biomarker for AD has been underestimated in the past; 1) specifically targeting MTL structures known to be sequentially involved by early AD pathology in asymptomatic patients, 2) novel parallel transmission MRI technology to obtain accurate diffusion data in the MTLs, 3) advanced models of T2 relaxation, diffusion kurtosis and white matter microstructure to better detect local changes in functional tissue organization by AD pathology. Results may warrant further NIH-supported investigation of region-specific targeted MRI as a noninvasive biomarker to diagnose underlying AD pathology and disease progression for asymptomatic patients.